Genetic analysis of intrinsic sensory neuron function in the enteric neural circuits

总结 胃肠道（GI）是唯一的腹部器官，已演变与自己的肠神经系统 (ENS)完全包含在肠壁内，也被称为肠道中的“第二大脑”。我们的长期目标是 了解ENS中的内在初级感觉神经元（IPAN）如何检测和响应两种物理刺激。 和化学线索，并控制结肠内容物的推进。 虽然IPAN已经被发现了25年，但它仍然是ENS中最神秘的神经元的一个子集。 因为它们如何参与协调的肌肉运动（运动），调节免疫细胞功能 （免疫力）和维持肠屏障完整性的机制尚未完全了解。同样神秘的是 IPAN是否能实现“模式发生器”的功能，并能控制周期性的节律性， 沿着结肠沿着传播收缩。这在很大程度上是由于缺乏可用于有选择地 操纵特定类别的肠神经元的兴奋性，以及任何试图 刺激或阻止IPAN中的活动可能会作用于许多其他类型的神经元（或非神经元细胞）， 使得对结果的解释不清楚。 在试点研究中，我们获得了关键资源，使我们能够识别和选择性地针对β- CGRP表达（β-CGRP+）IPAN。通过使用这些独特的资源，我们将能够要求重要的 关于β-CGRP+ IPAN在ENS中的作用的问题：β-CGRP+ IPAN在ENS中的作用是什么？ 神经活动沿着肠道传播这些IPAN是由机械和化学信号激活的吗 在肠腔里吗这些IPAN可以作为不同微生物衍生代谢物的细胞传感器吗？ 这项提议代表了一项重大的技术进步，它使用了尖端的神经遗传学方法， 使基因靶向和确定ENS中β-CGRP+ IPAN的功能成为可能， 离体和体内，提供了第一个洞察如何选择性激活和抑制β-CGRP+ ENS中的IPAN影响GI运动。这些信息将促进我们了解的内部运作， ENS并为治疗运动相关GI的新策略的开发提供了新的见解 通过靶向ENS中的IPAN来治疗疾病。

SUMMARY The gastrointestinal (GI) tract is the only abdominal organ that has evolved with its own enteric nervous system (ENS) fully contained within the gut wall, also known as the “second brain” in the gut. Our long-term goal is to understand how the intrinsic primary sensory neurons (IPANs) in the ENS detect and respond to both physical and chemical cues in the gut lumen and control propulsion of content in the colon. Although known for about 25 years, the IPANs are still a subset of the most mysterious neurons in the ENS because how they participate in coordinated muscle movements (motility), regulate immune cell function (immunity) and maintain integrity of intestinal barrier is not completely understood. Equally as mysterious is whether the IPANs can fulfil the function as a “pattern generator” and can control the rhythmicity of cyclical propagating contractions along the colon. This is largely due to a lack of tools that can be used to selectively manipulate the excitability of specific classes of enteric neurons and any drugs that have been tried to stimulate or block activity in IPANs will likely act on many other types of neurons (or non-neuronal cells), making interpretation of the results unclear. In pilot studies, we have generated critical resources enabling us to identify and selectively targeting the β- CGRP-expressing (β-CGRP+) IPANs. By using these unique resources, we will be able to ask important questions regarding the roles of the β-CGRP+ IPANs in the ENS: What role the β-CGRP+ IPANs have in the propagation of neural activity along the gut? Are these IPANs activated by both mechanical and chemical cues in the gut lumen? Can these IPANs serve as cellular sensors for distinct microbiota-derived metabolites? This proposal represents a major technical advance by using cutting-edge neurogenetic approaches which make it possible to genetically target and determine the functionality of the β-CGRP+ IPANs in the ENS both ex vivo and in vivo, providing the first insights into how selective activation and inhibition of the β-CGRP+ IPANs in the ENS affects GI-motility. This information will advance our understanding of the inner workings of the ENS and shed new insights on the development of novel strategies for the treatment of motility-related GI disorders by targeting the IPANs in the ENS.